Process for making polymorphic form A of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid

ABSTRACT

Process for making a pharmaceutical composition, comprising: a compound of formula (1) in crystalline form: 
                         
together with a pharmaceutically acceptable carrier or excipient,
 
     wherein the compound of formula (1) is present in polymorphic crystal form A substantially free of other polymorphs, and methods for making this polymorph.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The polymorphic form A, as defined by powder x-ray diffraction, of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid has high solubility and bioavailability compared to othercrystalline forms.

2. Description of the Background

Leukotrienes are metabolites of arachidonic acid through the5′-lipoxygenase pathway and are important mediators of allergicresponse, such as that involved in bronchial asthma. Drugs that exertantagonistic effects on the leukotrienes are useful for the treatment ofallergic diseases.

The synthesis and biological activity of many phenoxyalkylcarboxylicacid derivatives, which are leukotriene antagonists, are described byOhashi et al., U.S. Pat. No. 4,985,585. The compounds were obtained inlaboratory scale amounts by silica-gel column chromatography of thecrude product mixtures. The solvent was evaporated to give either a paleyellow oil or colorless crystals and no deliberate effort was made tocontrol crystal morphology.

We have observed that4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid (1), which is Example 33 in Ohashi et al., is orally active fortreatment of asthma and allergic diseases and that the solid compoundcan crystallize into several distinct polymorphs when prepared in bulk.It has been discovered that the crystallization conditions, particularlytemperature, is critically important for preparing the differentpolymorphs.

We have also found that the solubility and the bioavailability of one ofthese polymorphs, identified as orthorhombic crystals (Form V in Table1, and Form A in FIG. 6), is superior to the other polymorphs and thusform A offers improved solid formulations.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising acompound of formula (1) in a selected crystalline form:

together with a pharmaceutically acceptable carrier or excipient,wherein the selected crystalline form is composed of polymorphic form A,substantially free of undesired polymorphs. By “substantially free” ismeant that little or no undesired polymorphs are detectable by powderX-ray diffractometry (PXRD). Typically, the polymorphic purity isgreater than 90% (defined by peak heights in the powder x-raydiffraction trace). Preferably, the desired crystalline form of theinvention is at least about 95% of the polymorphic form A (FIG. 6) asmeasured by relative peak heights in the region of 9° 2-theta.

The present invention also provides a process for obtaining form A ofthe compound of formula (1) in at least about 90% purity with respect toother polymorphs. An exemplary crystallization process includes thesteps of dissolving compound (1) in 5 to 10 parts by weight of warmethanol and 1–10 parts of water, agitating the resulting suspension at20–25° C. for 15–60 minutes and then cooling to 5–10° C. for anadditional period of 1–4 hours, adding 5–15 parts of water, agitatingthe mixture at 5–10° C. for an additional 1–4 hours, and isolatingcrystals of compound (1) containing at least about 90% by weight of formA (FIG. 6).

Accordingly, a method for crystallizing the compound of formula (1) isprovided, which method comprises:

-   dissolving compound (1) in 5 to 10 parts by weight of ethanol and    1–10 parts of water, agitating the resulting suspension at 20–25° C.    for 15–60 minutes and then cooling to 5–10° C. for an additional    period of 1–4 hours,-   adding to this suspension 5–15 parts of water and agitating the    mixture at 5–10° C. for an additional 1–4 hours,-   isolating crystals of compound (1) in polymorphic Form A,    substantially free of other polymorphic forms. In a preferred method    of the invention the isolated crystals of compound (1) contain at    least about 90% of polymorphic Form A with respect to other    polymorphic forms. The isolated crystals of compound (1) in a    preferred embodiment exhibit a PXRD pattern substantially as shown    for polymorphic Form A in FIG. 6. Moreover, the isolated crystals of    compound (1) are at least about 90% polymorphic Form A, as defined    by PXRD peak heights around 90° 2-theta. The desired, i.e., in a    preferred embodiment, isolated crystals of compound (1) have a    substantially orthorhombic crystal structure.

Yet another method of the invention, the crystallization of a compoundof formula (1) is effected by steps comprising:

-   dissolving said compound in 5 to 7 parts by weight of ethanol at    30–40° C. and adding 1–2 parts of water, cooling the mixture to    10–15° C. over 2–3 hours and then cooling to 5–10° C. for an    additional period of 1–4 hours,-   adding to this suspension 5–15 parts of water and agitating the    mixture at 5–10° C. for an additional 1–4 hours, and isolating    crystals of compound (1) in polymorphic Form A, which is    substantially free of other polymorphic forms. Once more, in a    preferred method, the isolated crystals of compound (1) exhibit at    least about 90% of polymorphic Form A with respect to other    polymorphs. Preferably, the isolated crystals of compound (1)    exhibit a PXRD pattern substantially as shown for polymorphic Form A    in FIG. 6. Also, preferred isolated crystals of compound (1) are at    least about 90% polymorphic Form A, as defined by PXRD peak heights    around 9° 2-theta. More preferably, the isolated crystals of    compound (1) obtained by the instant method have a substantially    orthorhombic crystal structure.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Powder X-ray Diffraction Pattern and DSC Chart of Form I

FIG. 1 a DSC Chart of Form I

FIG. 2 Powder X-ray Diffraction Pattern and DSC Chart of Form II

FIG. 3 Powder X-ray Diffraction Pattern and DSC Chart of Form III

FIG. 4 Powder X-ray Diffraction Pattern and DSC Chart of Form IV

FIG. 5 Powder X-ray Diffraction Pattern and DSC Chart of Form V

FIG. 6 X-ray diffraction patterns of three polymorphs.

FIG. 7 Schematic process for dry granulation

FIG. 8 Schematic process for wet granulation

DETAILED DESCRIPTION OF THE INVENTION

Ester (4) can be synthesized by reacting a phenol of formula (2):

wherein R is an acid protecting group, such as methyl or ethyl, with thebromo compound of formula (3):

in an organic solvent, for example acetone, methylethylketone,diethylketone or dimethylformamide. The reaction may be conducted frombelow room temperature up to the reflux temperature of the solvent, inthe presence of an inorganic base, e.g., potassium carbonate or sodiumcarbonate. The addition of potassium iodide is also recommended.Analogues of compound (3) having alternative leaving groups, such aschloro and tosylate, may be used to effect the coupling reaction.

Removal of the acid protecting group by alkaline ester hydrolysis andextractive work-up gives compound (1) as a white solid.

Recrystallization of the white solid to give essentially pure form Acrystals (FIG. 6), (e.g., 90% or more, preferably at least 95%) can beaccomplished by dissolving compound (1) in 5 to 10 parts by weight ofethanol at 25–40° C. to give a yellow to orange solution. The ethanolsolution is charged with 1–10 parts of water and agitated at 20–25° C.for about 15–60 minutes and then at 5–10° C. for an additional period of1–4 hours, preferably 2.0–3.0 hours, resulting in an off-whitesuspension.

To this suspension is added 5–15 parts of water and the mixture isagitated at 5–10° C. for an additional 1–4 hours, preferably 1.5–2.0hours. A solid, white to off-white product is isolated by vacuumfiltration and the filter cake is washed with water and dried in avacuum at 25–40° C. for 12–24 hours.

Other recrystallization conditions are also able to produce form A, suchas dissolving compound (1) in a lower alcohol (isopropanol), and coolingthe solution form crystals.

Therapeutic Formulations

Pharmaceutical compositions containing the orthorhombic form of compound(1) may be formulated for oral administration with inert excipients,such as a starch binder excipient, alone or in combination withmicrocrystalline cellulose and a suitable lubricant. Other suitableexcipients include polyvinylpyrrolidinone, gelatin, hydroxy cellulose,acacia, polyethylene glycol, mannitol, sodium chloride, sodium citrateor any other excipient known to those of skill in the art ofpharmaceutical compositions.

Excipients in tablets are generally classified according to theirfunction, such as diluents (also called bulking agents and fillers),binders which hold the ingredients together in the compressed tablet,disintegrants which help facilitate the break-up of the tablet whenplaced in a fluid environment to release the active ingredient, andlubricants to improve the release of the compressed tablet from the dieand punches. In addition, tablets may contain other substances intendedto improve the tabletting process, such as flow additives, flavors,sweeteners and anti-oxidants

Tabletting and some capsule filling operations are based on the abilityof certain powders to bind under compression. Compressed tablets may beprepared by wet granulation, dry granulation, or direct compression. Thewet granulation process includes mixing the components in powder form,preparing the granulating binder solution, thoroughly mixing thecomponents with the granulating binder solution to form a dough, coarsescreening the mass through a sieve, drying, grinding, adding thelubricant and compressing the tablets from the resulting mixture.

A preferred tablet formulation is a wet granulation containingpolymorphic form A of compound (1) lactose regular, microcrystallinecellulose 101, crosscarmellose, magnesium stearate and purified water,coated with Opadry II white. The tablets should weigh from 100 mg to1000 mg, preferably 250 mg to 500 mg.

Dry granulation involves the steps of mixing the powder components,compressing the mixture into hard slugs, grinding the slugs into desiredparticle size, screening, adding other excipients if necessary, andcompressing the mixture into tablets. The most economical tablettingmethod, direct compression, requires only two steps, mixing the drycomponents and compressing the mixture into tablets.

Suitable direct compression binders include microcrystalline cellulose,compressible sugars, certain calcium salts, lactose and dextrose. Ofthese, microcrystalline cellulose is preferred. That excipient alsodisplays good disintegration properties. Other good binders includecalcium phosphates and compressible sugars. Calcium salt bindersgenerally require the use of disintegrants. Mannitol and sorbitol havecertain taste advantages, but they lack binding properties and require adisintegrant.

The tablets typically exhibit a tablet hardness of greater than 2kilopond (kp)/cm.sup.2, more preferably a tablet hardness of greaterthan 5, most preferably about 10 to about 20 kp/cm.sup.2 and adisintegration time of less than 30 minutes, more preferably less than15 minutes as measured utilizing the standard USP disintegration test inwater.

The polymorphic form A of compound (1) may also be formulated incapsules. Solid carriers include starch, lactose, calcium sulfate,di-hydrate, teffa alba, magnesium stearate or stearic acid, talc,pectin, acacia, agar or gelatin. The carrier may also include asustained release material such as glycerol monostearate or glyceroldi-stearate, alone or with a wax. The amount of solid carrier variesbut, preferably, will be between about 20 mg to about 1 gram per dosageunit.

Encapsulation can be done in any suitable manner, typically by use of apolymer coating used for microencapsulation, enteric coatings, multiplecoatings, and the like. The polymer coating may resist disintegrationupon contact with the saliva but instantly release the compound uponcontact with gastric juice in the stomach, in order to control the tasteof the composition. Alternatively, the polymer coating may be one thatresists rapid disintegration in the presence of gastric juice. Suitablecoating polymers include biodegradable polymers such as polylactic acid,polygycolic acid, copolymers of lactic and glycolic acid,polyorthoesters, and polyanhydrides thereof. The compound also can beencapsulated by a polymer coating such as a polysaccharide (e.g., methylor ethyl cellulose) or within a liposomal delivery system. Suitablemethods of preparing compositions containing microencapsulated activeingredients are described, for example, in U.S. Pat. Nos. 4,462,982,4,710,384, 5,178,878, and 5,709,886. Preferably, the microencapsulatedcompounds have a mean particle size of about 50 microns to about 120microns (e.g., about 70 microns to about 100 microns).

Typical doses of compound (1) in tablets and capsules are from about 1.0mg/kg to about 100 mg/kg. Administration intervals vary with thepatient's age, weight and general condition. In general, the drug isadminister from one to four times daily.

EXAMPLES

In general, tablets are formed utilizing a carrier such as modifiedstarch, alone or in combination with 10% by weight of carboxymethylcellulose (Avicel). The formulations are compressed at from 1,000 to3,000 pounds pressure in the tablet-forming process. The tabletspreferably exhibit an average hardness of about 1.5 to 8.0 kp/cm.sup.2,preferably 5.0 to 7.5 kp/cm2. Disintegration time varies from about 30seconds to about 15 or 20 minutes. The following examples give specificembodiments of the invention but should not be construed as limiting itsscope.

Example 1 Synthesis of ethyl4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)-propoxy]-2-propylphenoxy]butyrate

To a stirred mixture of ethyl4-(6-acetyl-3-hydroxy-2-propylphenoxy)butyrate (1.6 g), potassium iodide(0.5 g) and potassium carbonate (1.45 g) in acetone (30 ml) was addeddrop wise a solution of4-(3-bromopropylthio)-2-hydroxy-3-propylphenyl-ethanone (1.9 g) inacetone (10 ml) with heating to reflux. After refluxing six hours themixture was cooled to room temperature and inorganic materials wereseparated by filtration. The filtrate was concentrated and the residuewas separated and purified by silica-gel column chromatography (elutingwith benzene:ethyl acetate=9:1) to give the title compound as crudecrystals (2.1 g, 72.4%) which were recrystallized from ethanol to givecolorless crystals, mp 65–66° C.

Example 2 Synthesis of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid

To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (2.1 g) in ethanol(10 ml) was added a solution of sodium hydroxide (0.26 g) dissolved intowater (10 ml). After heating on a hot water bath for 5 minutes, themixture was cooled by adding ice-water and was made acidic by additionof hydrochloric acid, followed by extraction with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated. The resultant residue was separated and purified bysilica-gel column chromatography (eluting with ethanol:methylenechloride=3:100) to give the title compound (1.3 g, 65.2%) as colorlesscrystals, mp 79–81° C.

Example 3 Crystalline Polymorphism

After re-crystallization with individual solvents, compound (1) wassubjected to powder X-ray diffractometry, thermal analysis anddetermination of solubility in ether; thus an exploratory evaluation ofthe crystalline polymorphism was made. The results demonstrate thatcompound (1) is present in 5 different crystalline polymorphs.

FIGS. 1–5 show the powder X-ray diffraction patterns and DSC formetastable crystal types I through V. Table 1 shows the preparatoryprocedures for types I through V and their solubility in ether.

TABLE 1 Preparation of Crystalline Polymorphs and Their Solubilities inEther Crystal Solubility form Preparatory procedures (mg/mL) I Aftercompound (1) was heated and dissolved in a 4-fold quantity 36.7 ofisopropyl ether, the resultant solution was allowed to cool at roomtemperature (crystallization took place in the vicinity of 40° C.).Alternatively, after the compound was heated and dissolved in a 5-foldquantity of acetonitrile, the resultant solution was maintained at 40°C. in an incubator. II After compound (1) was heated and dissolved in a10-fold quantity 40.5 of acetonitrile, the resultant solution was cooledand agitated in an ice water bath. III After compound (1) was heated anddissolved in a 10-fold quantity 35.3 of acetonitrile, the resultantsolution was maintained at 25° C. in an incubator. IV After compound (1)was heated and dissolved in a 5-fold quantity 45.8 of ethanol, a2.5-fold quantity of water was added thereto while hot, which was thenallowed to cool at room temperature. V After compound (1) was heated anddissolved in a 5-fold quantity 47.6 of ethanol, the resultant was cooledand agitated in an ice water bath, and a 2.5-fold quantity of water wasadded thereto while cold. Alternatively, compound (1) was heated anddissolved in a 3.5-fold quantity of isopropanol and the resultingsolution was maintained at 0° C. in a refrigerator.

Table 1 shows that the crystallization temperature was criticallyimportant in preparing the various crystalline polymorphs. When the bulkingredient is prepared, crystallization takes place on a large scale andfailure in controlling the exact temperature can result in a mixture ofstable and metastable crystals, giving a larger variance in thephysicochemical properties and bioavailability among production lots,against which precautions should be taken.

Example 4 Bulk Crystallization Procedure for Obtaining OrthorhombicPolymorph, Crystal Type V (Form A)

Off-white solid compound (1) 34 g was dissolved in 204 mL (6 parts wrtmass of dry filter cake) of ethanol (40° C.) giving a yellow to orangesolution. With moderate agitation, the ethanol solution was charged with43 mL (1.3 parts) of water. The reaction mixture was cooled to 20–25° C.and agitated at 20–25° C. for about 15 minutes and then at 10–15° C. foran additional period of 1–2 hours, appearing as an off-white suspension.

To the resulting suspension was then charged 364 mL (10.7 parts) ofwater and the mixture was agitated at 5–10° C. for an additional 1–2hours. A solid, white to off-white product was isolated by vacuumfiltration. The filter cake was washed with 2×30 mL of water. The offwhite solid was dried in a vacuum at 35–40° C. for 24 hours.

Example 5

Solubility data of compound (1) in ethanol/water (2:1) desired undesiredpolymorphic form monoclinic temperature V (form A) polymorph 22° C.  6.7g/L 3.4 g/L 30° C. 15.7 g/L 6.1 g/L 40° C.   46 g/L 17.2 g/L 

Samples of compound (1) (5 g) were suspended in ethanol/water (2:1, 100mL) and stirred for one hour at temperatures of 22° C., 30° C., and 40°C., respectively. The suspensions were filtered and the solids dried ina vacuum oven at room temperature overnight to give the insolublematerial. The solubilities were calculated by subtractive means based onrecovered material.

Example 6

In general wet granulation tablets were prepared with a binding solutioncomprised of an aqueous solution of hydroxypropylcellulose. Granulationwas performed with a high shear granulator, the resultant wet mass wasfluid bed dried, milled, blended with extragranular excipients to aiddisintegration, flow and compressibility, and subsequently tabletted ona tablet press. These core tablets were film coated to standardizeappearance and to improve compliance (i.e. ease of swallowing).Excipients included, but were not limited to croscarmellose sodium,magnesium stearate, hydroxypropylcelluse, hydroxypropylmethylcellulose,lactose, glyceryl behenate, polyvinylpyrrolidine, mannitol,titaniumdioxide and microcrystalline cellulose.

Example 7

In general, the dry granulation formulation was formed by dry blending(in a tumble blender or high shear mixer) a portion of the binding,disintegration and lubrication powders. This dry powder blend was formedinto granules through the use of a roller compactor equipped with anoscillating (shear) granulator. The ss mesh screen, gap width, gapforce, roller speed and granulator speeds were defined to optimize theformulation physical parameters as apparent to those skilled in the artof pharmaceutical processing. Excipients included, but were not limitedto croscarmellose sodium, magnesium stearate, hydroxypropylcelluse,hydroxypropylmethylcellulose, lactose, glyceryl behenate,polyvinylpyrrolidine, mannitol, titanium dioxide and microcrystallinecellulose.

Example 8 Specific Formulation for Dry Granulation

TABLE 3.4.1 Proposed initial formulation compositions for drygranulation prototyping Prototype 1 Prototype 2 No. Ingredient(mg/tablet) (mg/tablet) 1 Compound (1), Type V (Form A) 250 250 2Lactose regular/fast flow 7.5 — 3 Microcrystalline cellulose PH101 31 314 Croscarmellose sodium 20 20 5 Hydroxypropylcellulose 80 — 6 Magnesiumstearate 2.0 — 7 Hydroxypropylmethylcellulose 2910 8.0 — 8 TitaniumDioxide 1.0 — 9 Carnauba wax 0.5 0.5 10 Polyvinylpyrrolidone — 85 11Mannitol — 3.5 12 Glyceryl behenate — 2.0 13 Opadry II (white) — 8.0Total 400 mg 400 mg The dry granulation process is given in the chart inFIG. 7.

Example 9 Specific Formulation for Dry Granulation

TABLE 3.4.2 Proposed initial formulation compositions for wetgranulation prototyping Prototype 3 Prototype 4 No. Ingredient(mg/tablet) (mg/tablet) 1 Compound (1), Type V (Form A) 250 250 2Lactose regular/fast flow 7.5 — 3 Microcrystalline cellulose PH101 32 324 Croscarmellose sodium 25 25 5 Hydroxypropylcellulose 25 — 6 Magnesiumstearate 2.0 — 7 Hydroxypropylmethylcellulose 2910 7.0 — 8 TitaniumDioxide 1.0 — 9 Carnauba wax 0.5 0.5 10 Polyvinylpyrrolidone — 30 11Mannitol — 3.5 12 Glyceryl behenate — 2.0 13 Opadry II (white) — 7.0Total 350 mg 350 mg The wet granulation process is given in the chart inFIG. 8.

The preferred embodiments of the invention have been described above indetail. Various modifications and improvements thereto will becomereadily apparent to those skilled in the art. The foregoing examples areintended to be non-limiting and exemplary of the invention described inthe foregoing specification and claimed below.

Example 10 PXRD Analysis

The samples were prepared by a normal front packing technique and run ona Siemens D5000 Diffractometer System. A high-resolution Cu—Kα-sourcewas used, operating at 50 kV/35 mA. The secondary beam wasmonochromatized by a Kevex solid state detector. The step scan mode wasused for data collection within the range of 2.5°–35° (2-theta). Theobtained data were processed by Diffrac Plus™ Software.

The parts of the diffraction patterns of three different polymorphs areshown in FIG. 6, determined as Form A (likely an orthorhombic structure,specified type V), Form B (I) and Form C (II) (both monoclinic lattices)are also shown.

As on can see the top pattern is quite different from the other two. Thedifferences are clearly marked with arrows above the top trace. Most ofthe single peaks on the upper pattern became doublets on the other two.This strongly suggests a structural transition with lowering of theoverall symmetry. In order to find out some criteria for betterdistinguishing of these polymorphous, an attempt for indexing theunknown lattices was performed. The results reveal an orthorhombiclattice (top trace, Form A) and a monoclinic one (middle trace, Form B).The bottom trace (Form C) has also a monoclinic lattice very similar tothat one of Form B, but with some missing reflections (marked witharrows) that could result from some structural differences.

The structure of our Form A is very close to Form V in Table 1 and FIG.5, although there are some differences at the range 19–25° 2-theta. Onthe other hand, the diffraction patterns for polymorphous Form I andForm II match well with Forms B and C, as they all apparently show thesplitting of the main reflections due to reducing the overall symmetryfrom orthorhombic to monoclinic.

Because crystallographic characterizations of all five polymorphousdescribed in Table 1 are difficult to reproduce, we will characterizethe structural state of compound (1) in pharmaceutical samples only bymeans of its appearance as Form A, as defined by PXRD.

1. A method of providing isolated orthorhombic crystalline4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which orthorhombic crystalline form (i) is substantially free ofmonoclinic crystalline forms as evidenced by powder x-ray diffraction(PXRD) analysis showing the absence of doublet peaks between about 11.5and 16 (2-Theta scale), and (ii) exhibits at least twice the solubilityof a monoclinic crystalline form at 30° C. in aqueous ethanol,comprising: (a) dissolving4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid in 5 to 10 parts by weight of ethanol and 1 to 10 parts of wateragitating the resulting suspension at 20–25° C. for 15–60 minutes andthen cooling to 5–10° C. for an additional period of 1–4 hours; (b)adding to this suspension 5 to 15 parts of water and agitating themixture at 5–10° C. for an additional period of 1–4 hours; and (c)isolating orthorhombic crystals of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which are substantially free of monoclinic crystalline forms.
 2. Amethod of providing isolated orthorhombic crystalline4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which orthorhombic crystalline form (i) is substantially free ofmonoclinic crystalline forms as evidenced by powder x-ray diffraction(PXRD) analysis showing the absence of doublet peaks between about 11.5and 16 (2-Theta scale), and (ii) exhibits at least twice the solubilityof a monoclinic crystalline form at 30° C. in aqueous ethanol,comprising: (a) dissolving4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid in 5 to 7 parts by weight of ethanol at 30–40° C. and adding 1–2parts of water, cooling the mixture to 10–15° C. over 2–3 hours and thencooling to 5–10° C. for an additional period of 1–4 hours. (b) adding tothis suspension 5–15 parts of water and agitating the mixture at 5–10°C. for an additional period of 1–4 hours; and (c) isolating orthorhombiccrystals of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which are substantially free of monoclinic crystalline forms.
 3. Amethod of isolating orthorhombic crystalline4-[6-acetyl-3-[3-(4-acetyl-3hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which orthorhombic crystalline form is substantially free ofmonoclinic crystalline forms, comprsing: (a) dissolving4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid in ethanol; (b) adding water and cooling the resulting mixturefirst to about 10–15° C. and second to about 5–10° C., (c) adding morewater and agitating the resulting mixture at about 5–10° C., and (d)isolating orthorhombic crystals of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which are substantially free of monoclinic crystalline forms.
 4. Amethod of recrystallizing4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, comprising: (a) dissolving4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid in 5 to 10 parts by weight of ethanol at about 25–40° C.; (b)adding 1–10 parts of water and agitating at 20–25° C. for about 15–60minutes; c) cooling to about 5–10° C. for a period of 1–4 hours; d)adding 5–15 parts of water and agitating at about 5–10° C. for a periodof about 1–4 hours; and e) isolating orthorhombic crystals of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which are substantially free of monoclinic crystalline forms. 5.The method of claim 4 in which the cooling of step (c) is carried outfor a period of 2–3 hours.
 6. The method of claim 4 in which theagitating step (d) is carried out for a period of 1.5–2 hours.
 7. Amethod of recrystallizing4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, comprising: a) dissolving4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid in 5 to 10 parts by weight of ethanol at about 25–40° C.; b) adding1–10 parts of water; c) agitating at 20–25° C. for about 15–60 minutes;d) agitating at about 5–10° C. for a period of about 1–4 hours; e)adding 5–15 parts of water; f) agitating at about 5–10° C. for a periodof about 1–4 hours; and g) isolating orthorhombic crystals of4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which are substantially free of monoclinic crystalline forms.
 8. Amethod of preparing a pharmaceutically acceptable tablet or capsulecontaining isolated orthorhombic crystalline4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which orthorhombic crystalline form is substantially free ofmonoclinic crystalline forms, comprising: a) combining pharmaceuticallyacceptable components of a tablet or capsule, including isolatedorthorhombic crystalline4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyricacid, which orthrohombic crystalline form is substantially free ofmonoclinic crystalline forms, to provide a mixture; and b) compressingthe mixture into a tablet of filling a capsule with the mixture.
 9. Themethod of claim 8 which further comprises a wet granulation step or adry granulation step prior to the compression step in the case of atablet.